Canine olfactory detection and its relevance to medical detection

Abstract

The extraordinary olfactory sense of canines combined with the possibility to learn by operant conditioning enables dogs for their use in medical detection in a wide range of applications. Research on the ability of medical detection dogs for the identification of individuals with infectious or non-infectious diseases has been promising, but compared to the well-established and–accepted use of sniffer dogs by the police, army and customs for substances such as money, explosives or drugs, the deployment of medical detection dogs is still in its infancy. There are several factors to be considered for standardisation prior to deployment of canine scent detection dogs. Individual odours in disease consist of different volatile organic molecules that differ in magnitude, volatility and concentration. Olfaction can be influenced by various parameters like genetics, environmental conditions, age, hydration, nutrition, microbiome, conditioning, training, management factors, diseases and pharmaceuticals. This review discusses current knowledge on the function and importance of canines’ olfaction and evaluates its limitations and the potential role of the dog as a biomedical detector for infectious and non-infectious diseases.

Full text

Jendrnyetal. BMC Infect Dis (2021) 21:838
https://doi.org/10.1186/s12879-021-06523-8
REVIEW
Canine olfactory detection andits relevance
tomedical detection
Paula Jendrny1, Friederike Twele1, Sebastian Meller1, Albertus Dominicus Marcellinus Erasmus Osterhaus2,
Esther Schalke3 and Holger Andreas Volk1*
Abstract
The extraordinary olfactory sense of canines combined with the possibility to learn by operant conditioning enables
dogs for their use in medical detection in a wide range of applications. Research on the ability of medical detection
dogs for the identification of individuals with infectious or non-infectious diseases has been promising, but compared
to the well-established and–accepted use of sniffer dogs by the police, army and customs for substances such as
money, explosives or drugs, the deployment of medical detection dogs is still in its infancy. There are several factors
to be considered for standardisation prior to deployment of canine scent detection dogs. Individual odours in disease
consist of different volatile organic molecules that differ in magnitude, volatility and concentration. Olfaction can
be influenced by various parameters like genetics, environmental conditions, age, hydration, nutrition, microbiome,
conditioning, training, management factors, diseases and pharmaceuticals. This review discusses current knowledge
on the function and importance of canines’ olfaction and evaluates its limitations and the potential role of the dog as
a biomedical detector for infectious and non-infectious diseases.
Keywords: Biomedical detection dogs, Olfaction, Olfactory sense, Screening method, Sniffer dogs
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Background
Canines are macrosmatics with an extraordinary olfac-
tory sense and memory [1, 2]. Olfaction is mandatory
for the dog to perceive environmental information,
which has been used successfully by humans for track-
ing and detection of pest and prey animals and other
food sources [3]. Routinely, dogs nowadays are pre-
dominantly deployed for the identification of explosives,
drugs, currencies, people, endangered animal species and
parasites [4]. In recent years, medical scenting dogs have
been trained to detect different medical conditions, but
this area of work is still relatively in its infancy [5]. e
use of odour detection as a diagnostic tool is of increas-
ing interest in recent [5, 6]. is review will summarise
information on odour origin and composition, neuro-
anatomy and physiology of the canine olfaction, differ-
ent impacts on the olfactory sense and majorly current
research outcomes critically evaluating the possible role
of the dog as a biomedical detector.
Methods
Search strategies for this review included electronic
search engines for publication databases, searching ref-
erence lists of published papers and information from
relevant scientific conferences and discussion groups.
For the section about biomedical detection dogs three
databases (Google Scholar, Science Direct and PubMed)
were searched for studies reporting the training, testing
and deployment of biomedical detection dogs between
2004 and 2021. e searches were performed by the
authors using the following keywords: “biomedical detec-
tion dogs” or “detection dogs” or “canines” in combina-
tion with “infectious diseases”, “non-infectious diseases”,
Open Access
*Correspondence: holger.volk@tiho-hannover.de
1 Department of Small Animal Medicine and Surgery, University
of Veterinary Medicine Hannover, Bünteweg 9, 30559 Hannover, Germany
Full list of author information is available at the end of the article
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“malaria”, “SARS-CoV-2”, “COVID-19”, “hypoglycaemia”,
“epileptic seizure”, “cancer”, “bacteria” or “viral”. Peer-
reviewed studies and pre-prints published in English and
results presented at the WHO R&D Blueprint COVID-19
consultation [6] were evaluated. Literature that addressed
detection rate and/or diagnostic accuracy (sensitivity and
specificity) of biomedical detection dogs without restric-
tions to year of publication was included in this review
article. Only double-blinded and randomised studies for
SARS-CoV-2 detection were reported in this study.
Main text
Research onbiomedical detection dogs
e use of biomedical detection dogs for various infec-
tious and non-infectious diseases like Helicobacter pylori
[7], different cancer types [8–17], hypoglycaemia in dia-
betes mellitus patients [18–20], epileptic seizures [21],
bacteriuria [22], bovine virus diarrhoea [23], COVID-19
[24–33], Malaria [34] and Clostridium difficile-infections
[35] is still in its infancy (Table1). Most of these studies
indicate a disease-specific body odour or a specific vola-
tile organic compound (VOC)-pattern associated with
metabolic changes secondary to an infection [36]. In case
of an infection with a virus, VOCs are generated purely
by the host cell, but for bacteria, VOCs are generated
by the host and the bacteria respectively [36]. For many
diseases the exact odour molecules that are recognised
and indicated by dogs remain unknown. Disease-specific
VOC-patterns have been identified in diseases such as
asthma, several types of cancer, cystic fibrosis, diabe-
tes mellitus, dental diseases, gastrointestinal diseases,
heart allograft rejection, heart diseases, liver diseases,
pre-eclampsia, renal disease, cholera and tuberculosis
[36–38].
Canine medical scent detection appears more promis-
ing for infectious diseases than non-infectious diseases
such as cancer, diabetes mellitus and epileptic seizures.
Despite some initially promising medical dog scent
detection studies, published data can vary significantly
for the identification of cancer. Studies with trained
sniffer dogs achieved very different results in the identifi-
cation of different cancer types, such as bladder, prostate
or ovarian cancer, lung and breast cancer as well as colo-
rectal neoplasms. Diagnostic accuracies varied with sen-
sitivities ranging from 19 to 99% and specificities from
73 to 99% when compared to histopathology [8–17]. Dif-
ferent sample materials were used for presentation, e.g.
urine, blood, breath or faeces, which could explain the
variability in findings. Another influencing factor that
plays a role regarding the variability of the results is the
lack of standardisation of training and the trainer bias,
which may have a major influence on the training results
of detection dogs [39]. More published data about cancer
detection by dogs is reviewed elsewhere [40, 41].
Medical scent detection dogs have also been deployed
for patients with diabetic mellitus. Identifying hypogly-
caemic conditions is crucial for people with diabetes mel-
litus because of the potential severity of such a condition.
A drop of blood is required to measure blood glucose,
which is an invasive method that must be performed
consciously and regularly. Not every patient is able to
take blood themselves. e deployment of a hypoglycae-
mia sniffer dog is a non-invasive method, but satisfactory
results have not been achieved. e researchers found
sensitivities between 36% [20] and 88% [42] and specifi-
cities of 49% [19]–98% [42] compared to the standard
method blood glucose measurement via blood glucose
meter.
e prediction of an epileptic seizure could help the
affected person to find a safe environment before the
seizure begins or to take emergency medication. It is
assumed that canines have the ability to detect an altera-
tion of the body odour. Due to a high variability of the
types and causes of epilepsy, it is still unknown which
specific odour the dogs detect but chemical analyses
could identify seizure-specific odour molecules [21].
In another study using sweat of persons with epilepsy,
canines distinguished between interictal and ictal sweat
with a probability of 93% and warned the individual
before a clinical seizure occurred with a probability of
82% [43]. Some studies also report seizure alerting dogs
that did not undergo any systematic training [44–46].
ese dogs may detect specific odour-alterations as well
as visual cues or behavioural changes of the person with
epilepsy [44–46].
Studies including the detection of infectious diseases
by dogs appear to be more promising. e training of
detection dogs in the following studies was reward-
based (based on positive reinforcement). Guest et al.,
2019, performed a study for the detection of protozoal
Malaria to develop a non-invasive screening method for
infected individuals [34]. Even in asymptomatic chil-
dren the dogs had a sensitivity and specificity of 72% and
91%, respectively. Previously worn nylon socks were pre-
sented to the two trained dogs. e results were higher
than the threshold for WHO malaria diagnostics [34].
e training of dogs to identify bacterial infections like
bacteriuria in urine [22] or Clostridium difficile in stool
samples [35] also generated promising results. Mau-
rer et al., 2016, trained dogs to improve strategies for
detecting early stages of bacteriuria before the infection
becomes serious. e dogs detected different pathogens
(Escherichia coli, Enterococcus, Klebsiella, Staphylococ-
cus aureus) with an overall sensitivity of close to 100%
and specificity of above 90% [22]. For the detection of
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Table 1 Overview medical detection dog studies
Publication Authors Detection of Study design Sample material Sample size Results
Real-Time Detection of a
Virus Using Detection Dogs
[23]
Angle et al. (2016) Bovine viral diarrhea virus Randomised, blinded Cell culture n = 15 Sensitivity 91%
Specificity 99%
Trained dogs identify people
with malaria parasites by
their odour [34]
Guest et al. (2019) Malaria infection Randomised, blinded Body odour (socks) n = 175 Sensitivity 72%
Specificity 91%
Detection of Bacteriuria by
Canine Olfaction [22]Maurer et al. (2016) Bacteriuria Randomised, blinded Urine n = 687 Sensitivity near 100% Specific-
ity above 90%
Using Dog Scent Detec-
tion as a Point-of-Care
Tool to Identify Toxigenic
Clostridium difficile in Stool
[35]
Taylor et al. (2018) Toxigenic Clostridium difficile Randomised, blinded Faeces n = 300 Sensitivity 85%
Specificity 85%
Olfactory detection of
human bladder cancer by
dogs: Proof of principle
study [8]
Willis et al. (2004) Bladder cancer Randomised, blinded Urine n = 144 mean success rate 41%
Olfactory Detection of Pros-
tate Cancer by Dogs Sniff-
ing Urine: A Step Forward
in Early Diagnosis [9]
Cornu et al. (2011) Prostate cancer Randomised, blinded Urine n = 66 Sensitivity 91%
Specificity 91%
Key considerations for the
experimental training and
evaluation of cancer odour
detection dogs: lessons
learnt from a double-blind,
controlled trial of prostate
cancer detection [10]
Elliker et al. (2014) Prostate cancer Randomised, blinded Urine n = 181 Sensitivity 19%
Specificity 73%
A Proof of concept: Are
Detection Dogs a Useful
Tool to Verify Potential
Biomarkers Biomarkers for
lung cancer? [11]
Fischer-Tenhagen et al.
(2018) Lung cancer Randomised, blinded Absorbed breath samples n = 60 correct identification average
95%, correct negative indica-
tions average 60%
Accuracy of Canine Scent
Detection of Non–Small
Cell Lung Cancer in Blood
Serum [12]
Junqueira et al. (2019) Non–small cell lung cancer Randomised, blinded Blood serum n = 10 Sensitivity 97%, Specificity 98%
Diagnostic accuracy of
canine scent detection in
early- and late-stage lung
and breast cancers [14]
McCulloch et al. (2006) Lung and breast cancer Randomised, blinded Breath n = 169 Lung cancer: Sensitivity 99%
Specificity 99%
Breast cancer: Sensitivity 88%
Specificity 98%
How dogs learn to detect
colon cancer-Optimizing
the use of training aids [15]
Schoon et al. (2020) Colon cancer Randomised, blinded Faeces n = 70 Average hit rate 84%
Average false positive rate 12%
(for new unknown samples)
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Table 1 (continued)
Publication Authors Detection of Study design Sample material Sample size Results
Colorectal cancer screening
with odour material by
canine scent detection [17]
Sonoda et al. (2011) Colorectal cancer Randomised, blinded Breath and faeces n = 350 Breath: Sensitivity 91%
Specificity 99%
Faeces: Sensitivity 97%
Specificity 99%
Cancer odor in the blood of
ovarian cancer patients:
a retrospective study of
detection by dogs during
treatment, 3 and 6 months
afterward [16]
Horvath et al. (2013) Ovarian cancer Randomised, blinded Blood plasma n = 262 Sensitivity 97%
Specificity 99%
Can Trained Dogs Detect a
Hypoglycemic Scent in
Patients With Type 1 Diabe-
tes? [123]
Dehlinger et al. (2013) Hypoglycaemia Blinded Skin odour n = 24 Sensitivity 56%
Specificity 53%
Dogs Can Be Success-
fully Trained to Alert to
Hypoglycemia Samples
from Patients with Type 1
Diabetes [42]
Hardin et al. (2015) Hypoglycaemia Randomised, blinded Sweat n = 56 Sensitivity 50%-88%
Specificity 90%-98%
How effective are trained
dogs at alerting their own-
ers to changes in blood gly-
caemic levels?: Variations in
performance of glycaemia
alert dogs [18]
Rooney et al. (2019) Hypoglycaemia Not applicable Breath and sweat Not applicable Median sensitivity 83%
Variability of Diabetes Alert
Dog Accuracy in a Real-
World Setting [19]
Gonder-Frederick et al. (2017) Hypoglycaemia Not applicable Body odour Not applicable Sensitivity 57%
Specificity 49%
Reliability of Trained Dogs
to Alert to Hypoglycemia
in Patients With Type 1
Diabetes [20]
Los et al. (2017) Hypoglycaemia Not applicable Body odour Not applicable Sensitivity 36%
Dogs demonstrate the exist-
ence of an epileptic seizure
odour in humans [21]
Catala et al. (2019) Epileptic seizure Pseudo-randomised, blinded Breath and sweat n = 5 Sensitivity 87%
Specificity 98%
Canine detection of volatile
organic compounds
unique to human epileptic
seizure [43]
Maa et al. (2021) Epileptic seizure Randomised, blinded Sweat n = 60 Probability of distinguishing
ictal versus interictal sweat
93%
Probability of canine detection
of seizure scent preceded
clinical seizure 82%
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toxigenic Clostridium difficile in stool samples, two dogs
were trained and achieved sensitivities of 78% and 93% as
well as specificities of 85%, respectively. e aim of this
study was to evaluate the dog method as a “point-of-care”
diagnostic tool [35]. Lastly, it was also possible to train
dogs to detect viral infections with bovine viruses [23] or
with the coronavirus SARS-CoV-2 in various body fluids
[6, 24–33] with high rates of diagnostic accuracy. Real-
time methods for the identification of viral infections are
often limited or not existing, especially for resource-lim-
ited environments. Angle etal., [23] examined the abil-
ity of two dogs to detect and discriminate bovine viral
diarrhoea virus cell cultures from cell cultures infected
with bovine herpes virus 1, bovine parainfluenza virus
and controls with high rates of sensitivity and specificity
(Table1).
Recently, there is a rapid, growing body of evidence for
detection dogs being used for identifying SARS-CoV-2
infected individuals [24–33]. In the SARS-CoV-2 detec-
tion dog studies, different sample material, study designs
and dog breeds were used in different countries. Most of
these studies achieved promising results (Table2). e
most common dog breeds used were Malinois, other
shepherd breeds and Labrador Retrievers. ese dogs
are specifically bred for scent detection, selected for
their scenting ability with an appropriate cognition and
motivation behaviour making them popular breeds for
biomedical detection [47]. e samples were collected
initially mainly from hospitalised COVID-19 patients,
but now as well as from asymptomatic and mildly symp-
tomatic infected individuals with a variety of symptoms.
Some researchers used distractors (samples from indi-
viduals suffering from other respiratory diseases than
COVID-19) in the training and testing phases, which
were slightly different from the target scent to better
represent conditions in the field where other respira-
tory diseases different from COVID-19 will be to be also
presented. A wide variety of human body fluids (saliva,
tracheobronchial secretions, urine, sweat) as well as
nasopharyngeal swabs, breath samples and masks or
clothing were used as sample materials for presentation
to dogs during training and testing [24–33]. Interestingly,
dogs trained with saliva samples were also able to detect
samples of infected individuals in sweat and urine with-
out further training which is indicative for a successful
generalisation process [25]. In detection dog training, it
is important to pay equal attention to generalisation and
discrimination. Generalisation means that after success-
ful training, the dog also reacts to new, unknown stimuli
that have similar odour properties to the training odour,
whereas discrimination means the ability to distinguish
between similar stimuli [48]. Without successful general-
isation by the dogs, they would memorise the individual
odours of the training samples individually and would
have great difficulty recognising new samples as positive
or negative. A lack of discrimination process would mean
that the dogs would not only indicate the specific disease
they were trained for, but would also indicate similar
odours, e.g. respiratory diseases other than COVID-19,
which would preclude the dog’s use as a screening
method.
e various sample materials differ in the ease of collec-
tion, VOCs contained and infectivity, e.g. sweat or urine
samples seem to be less infectious than saliva [49, 50].
Our own canine experience has shown that sensitivity
and specificity of each dog appeared slightly different for
each presented sample, but fairly similar overall for each
bodyfluid [25]. e reason for this could be that not every
dog learned the same VOC-pattern as being positive but
slightly different ones. When working with detection
dogs, it is not possible to know exactly to which specific
VOCs the dogs were conditioned to. It is also unknown
whether each dog had learned the same disease-specific
VOC-patterns as being positive. Nevertheless, the study
results of the different research groups indicate that all
dogs could be successfully conditioned to a specific virus-
induced odour, otherwise the results listed below could
not have been achieved [24, 25]. Most studies have not
pre-selected dogs, but this would be needed when using
them as a diagnostic test, with only the best performing
dogs being used.
Sensitivities in the different studies ranged from 65 to
100%, specificities from 76 to 99% (Table2).
e training and test design in the various studies dif-
fered, but the dog training in all of them was based on
positive reinforcement. As training and testing setup,
most of the studies included the dogs working on a line-
up with different numbers of samples presented. Sample
material from SARS-CoV-2 positive individuals was used
as target samples, negative controls were obtained from
healthy individuals and only some groups also used dis-
tractors (sample material from individuals suffering from
other respiratory diseases other than COVID-19) to train
and test the detection dogs.
Origin andcomposition ofodours
What are dogs scenting when they identify an infected
individual? e complex process of odour recognition
starts with the development and composition of odours
[51]. e majority of odours detected by dogs through
inhaling are VOCs in different compositions residing
in the air [51]. VOCs can differ in magnitude, volatility,
and concentration. e odour concentration in the air
correlates with the concentration of its source, volatil-
ity, the sources odour releasing surface area, the volume
flow rate, ambient air movements and diffusion velocity
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within its source [52]. On top of that and depending on
the materials in contact with specific odours, adsorption
or absorption of VOCs occurs which is important for
sampling and sample presentation for biomedical detec-
tion dogs. In general, liquids and plastic polymers absorb
odours whereas surfaces like metal, glass, wood and cot-
ton adsorb and release them [53].
e term ‘VOC’ describes atmospheric trace gases
except for carbon dioxide and monoxide. Biogenic VOCs
e.g. are isoprene and monoterpenes (most prominent
compounds), as well as alkanes, alkenes, carbonyls, alco-
hols, esters, ethers and acids [52], have a strong odour
and are produced as well as emitted by animals, plants
and micro-organisms. e VOC-pattern of an organ-
ism is governed by VOC-producing cells or tissues and
largely determined by its physiological or patho-physio-
logical metabolism, the latter being subject to exogenous
influences like infections, skin emanations or smokers’
breath [52]. Different diseases cause the emergence and
emission of more or less specific VOC-patterns [36],
which can be used as diagnostic olfactory biomarkers.
Abd El Quader et al. [54] identified pathogen-related
VOCs emanated from viral and bacterial cultures and
Steppert etal., [55] found a difference in emanated VOCs
between SARS-CoV-2 and Influenza-A infections in
human breath. Various possibilities of measuring spe-
cific VOCs are existent, such as gas chromatography
mass-spectrometric techniques (GC–MS) for identifica-
tion and characterisation [36]. e diagnostic potential
of scent detection dogs for VOC-based disease detection
has been discussed recently [51].
VOCs are liberated from various tissues and body flu-
ids. e most common body fluids or tissues for diagnos-
tic testing are skin emanations, urine, blood, saliva and
faeces differing in their VOC-composition [56]. Human
bodies emit an extensive repertoire of VOCs that vary
with age, diet, gender, genetics and physiological or
pathological status and can be considered as individual
attributes [36]. Pathological processes influence the
body odour either by producing new VOCs or by chang-
ing the VOC-pattern which dogs may be able to detect
[36]. During the training of biomedical detection dogs
it is therefore important that dogs are not conditioned
to the individual odours of the subjects or the environ-
ment were samples were produced (e.g. hospital smell)
but learn the disease-specific odour (VOC-pattern) and
successfully complete the generalisation process. It is also
important to emphasize that the biochemical origins for
some of the VOCs have not been completely elucidated
until now.
Neuroanatomy ofolfaction
e anatomical construction of the olfactory system is
highly structured in order to ensure efficient nasal odor-
ant transport as well as respiratory airflow [57]. e sen-
sory impression emerges through the olfactory system
[58]. e substantial elements of the canine olfactory sys-
tem are the outer nose with nares and nasal wings, nasal
cavity, the olfactory epithelium with receptors, the vome-
ronasal organ, the olfactory bulb and the olfactory cortex
of the cerebrum [58]. e bilateral nasal cavity is divided
in the median plane by the nasal septum. Each side
includes a nasal vestibule lined with cutaneous mucosa,
a respiratory and an olfactory region, but also comprises
a naso-, maxillo- (lined with respiratory epithelium and
a small number of olfactory neurons) and ethmotur-
binate (olfactory epithelium) to increase the olfactory
mucosal surface, especially in macrosmatics [58, 59]. e
three turbinates divide the nasal cavity’s chamber into
three meatuses of the nose, whereby the ventral meatus
is responsible for the respiration (inspiration and expi-
ration). e dorsal meatus leads to the olfactory organ,
whereas the middle nasal meatus terminates in the para-
nasal sinuses [58].
Figure1 shows the general structure of the olfactory
mucosa. All components between the lumen of the nasal
cavity and the cribriform plate are shown in simplified
form. e nasal cavity lining has the function to sepa-
rate odour molecules by their partition coefficients into
the mucosa [60] and to create different flow dynamics in
order to distribute odour molecules to the receptors, thus
patterning the odorants [61]. Olfactory molecules in the
nasal cavity lumen bind to olfactory receptors on the cilia
of olfactory receptor cells embedded between supporting
cells. e respiratory epithelium consists of a multi-row
ciliated epithelium with goblet cells [58]. e olfactory
epithelium implies a pseudostratified columnar neuro-
epithelium [62] located next to the cribriform plate and
lining the turbulate bones symmetrically in the nasal cav-
ity [63] with millions of olfactory receptor cells (ORC)
and olfactory receptors (OR), but also supporting susten-
tacular cells regulating the nasal mucous composition,
isolating the ORCs and protecting the epithelium from
inhaled potentially dangerous substances [64]. Moreover,
basal cells are located adjacent to the lamina propria in
the olfactory epithelium and comprise Bowman’s glands
in the lamina propria whose secretion builds a mucous
layer in combination with the sustentacular cells’ sub-
stances which maintain nasal humidity and capture odor-
ants [58, 62]. e lamina propria itself is adjacent to the
bony lamina cribrosa, which is traversed by olfactory
nerve fibres. e regular olfactory perception depends on
this area [64].
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An additional olfactory system can be found in the
vomeronasal organ of dogs (Fig.2).
Via unique airflow patterns, environmental odorants
selectively bind to the ORs to initiate odour perception
[59]. e ORC is a bipolar neuron: the dendrite extends
in the direction of the olfactory epithelium (nasal cavity)
and terminates with the ORs located in the membrane
of multiple cilia in the mucous layer, whereas the axons
of all ORCs build the olfactory ‘nerve’ (fila olfactoria)
passing through the cribriform plate and to the olfac-
tory bulb. e complex structure gives dogs the ability
to detect an enormous quantity of different odour mole-
cules with subtle shape, size or stereoisomeric differences
[65, 66]. e exact sequence of the olfactory process at
the molecular level has been reviewed elsewhere [58].
e glomeruli approach dendrites of mitral cells and
tufted cells whose axons constitute the lateral olfactory
tract that conducts the signal to the piriform cortex and
project it to the olfactory cortex in the medial temporal
lobes [64].
e olfactory cortex receives sensory signals from the
olfactory bulb. e processing of olfactory signals in the
brain is also beyond the scope of this review and can be
found elsewhere [58]. An overview of important olfac-
tory characteristics of dogs is presented in Table3.
Figure2 shows a comparison of the olfactory system
between dog and human. Components of the olfactory
system are shown in colour. Particularly noticeable are
the differences in extent, shape and position of the olfac-
tory bulbs and the vomeronasal organ, which is present
only in dogs but not in humans. It is located bilaterally
symmetric on the ventro-rostral bottom of the nasal cav-
ity behind the canine teeth and associated to the nasal
and oral cavity. Its sensory epithelium detects mainly
pheromones and non-volatile molecules for intra-spe-
cies-specific communication and reproduction. e
transmission follows a separate pathway directly to the
hypothalamus [59, 67]. Figure3 presents important inner
structure of the olfactory system.
Physiology ofolfaction anduid dynamics
Animals use olfaction to find and select nourishment or
prey [68, 69], for recognition of social partners, preda-
tors or environmental toxins as well as for orientation
and communication [36, 70]. Body odours function as
indicators of the metabolic status of individuals [36].
Table 2 Overview of SARS-CoV-2 detection dog studies
All included studies were double-blinded and randomised
Country Sample material Number of sample
presentations (test) Results
Sensitivity Specicity
France [26] Sweat n = 321 90% and 88% 90% and 85%
Germany [24, 25] Inactivated saliva/tracheobronchial
secretion n = 1012 83% 96%
Non-inactivated saliva n = 2513 82% 96%
Sweat n = 531 91% 94%
Urine n = 594 95% 98%
Iran [29] Nasopharyngeal n = 80 65% 89%
Masks and clothes n = 120 86% 93%
Colombia [28] Saliva/respiratory secretions n = 9200 89% 97%
Brazil [6] Not applicable Not applicable Not applicable Not applicable
United Arab Emirates [30] Axillary sweat n = 1368 92% 96%
United Arab Emirates [32] Sweat n = 3290 83% 99%
Argentina [6] Not applicable Not applicable 93% 89%
Australia [6] Not applicable Not applicable 100% 95%
Lebanon [6] Sweat Not applicable 100% 92%
Sweat (airport) Not applicable 96% 90%
Chile [6] Sweat Not applicable 90% 97%
Finland [6] Sweat, urine, saliva Not applicable 100% 91%
Belgium [6] Sweat Not applicable 81% 98%
United Kingdom [31] Breath and sweat n = 2261 82%-94% 76%-92%
USA [27] Saliva and urine n = 59 11–22% 94–100%
Urine 71% 99%
USA [33] Breath n = 160 Not applicable Not applicable
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Jendrnyetal. BMC Infect Dis (2021) 21:838
e canine’s scent detection ability limit for VOCs has a
reported range of parts per million and parts per trillion
[71]. Different types of airways in the canine nasal cavity
are shown in Fig.4.
In the cognition process of various stimuli, hemispheric
specialization takes place [72]. For the olfactory path-
way, it means, that olfactory stimuli ascend ipsilaterally
from the detection place in the nasal cavity to the place
of perception in the olfactory cortex [72]. Dogs use pref-
erentially the right nostril to detect conspecific arousal
or novel odours, transmitting sensory input to the right
cerebral hemisphere to process alarming stimuli. e left
nostril is preferentially used to sniff non-aversive, famil-
iar and heterospecific arousal odours as well as target
odours by detection dogs [73].
Current literature is not clear about breed-specific
olfactory capabilities and discusses the influence of
genetic polymorphism in comparison to behaviour and
trainability [47, 74, 75].
Factors impacting olfaction
ere are several circumstances which can affect the
olfactory sense of dogs [58]. Some are of physiological
origin, others are pathological. Especially when working
with biomedical detection dogs, it is important to know
these factors and adjust the working conditions for the
dogs as best as possible.
Physiological variation in the olfactory capability is
most frequently caused by differences in genetics. In gen-
eral, macrosmatic animals have an olfactory gene array of
greater extent, much larger than microsmatics. A com-
prehensive overview of the genetic influence on the sense
of smell in dogs can be found in the according literature
[76–81].
Differences in the olfactory capabilities of different dog
breeds and wolves are also described. Polgàr etal., [47],
compared detection abilities of dog breeds selected for
scenting abilities, dog breeds for other purposes, brachy-
cephalic dog breeds and hand-raised wolves. As a result,
the breeds selected for odour work (e.g. Shepherd Dogs
or Labradors) and in some tests even the wolves per-
formed better than the other dogs and the short-nosed
breeds.
Secondly, the environmental conditions influence the
odour sensing abilities. Relative humidity and baromet-
ric pressure may directly affect olfaction, besides their
effects on odour emergence and movement itself, while
heat has only indirect effects [58, 82–84]. Acclimatiza-
tion to the environment, physical fitness and an adequate
hydration state can prevent heat stress of the dogs [84].
Age can influence the sensory process [85]. Olfaction
and its cognition are impacted by age in humans [86] as
well as in dogs [58]. Age affects various functional parts
of the olfactory system in dogs at an age of older than
14years [86, 87].
Fig. 1 Schematic structure of the olfactory mucosa
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Jendrnyetal. BMC Infect Dis (2021) 21:838
Conditioning, training, and management play a major
role for the use of dogs as detection dogs [58]. Exer-
cise and condition deficiencies are described as physi-
cal stressors which may affect the olfaction in canines
directly or indirectly [58]. Physical exercise affects the
olfaction of detection dogs by decreasing finding rates,
especially in dogs with poor physical conditions [88,
89]. As a result, a working dog should be well trained
to have an optimal physical condition [90]. Scent detec-
tion training techniques can improve odour sensitivity
and discrimination [89–92]. Housing and general man-
agement may influence the dogs’ detection work as well
by affecting the learning capability. Lower stress levels
due to social contact and an enriched, secure environ-
ment were shown to enhance cognitive performance
[87]. Positive rewards with particularly tasty treats as
well as a specific toy in some dogs increase working
motivation of dogs whereas aversive training methods
decrease motivation and have also negative effects on
their physical and mental health [93].
Hydration [84], nutrition [88, 89], and the micro-
biome [58] of dogs manipulate the olfactory sense as
well. As mentioned above, heat stress influences olfac-
tion due to provocation of panting but dogs are able
to develop heat tolerance by establishing an adequate
hydration status [84, 89].
e nutritional factor influencing the olfactory sense
of dogs includes the feeding time, amount of food per
meal, ingredients like the fat/protein ratio and the fat
source [88, 89, 94–98].
Various diseases and medication can affect the olfac-
tion of dogs and lead to hyposmia or anosmia. More
information on hyposmia can be found elsewhere [58,
99].
Diseases or disorders potentially leading to hyposmia
or anosmia in humans and potentially in dogs [100] are
congenital and neurodegenerative diseases [86, 101],
metabolic, endocrine (hyperadrenocorticism, diabetes
mellitus, and hypothyreoidism [101]) and neurologi-
cal diseases like nasal/brain tumours, granulomatous
Fig. 2 Schematic structure of the olfactory system in dogs and humans
Table 3 Olfactory characteristics of dogs
Characteristics Dog
Airflow A sniff creates unique unidirectional laminar airflow patterns to transport environmental odor-
ants to the olfactory epithelium [122]
Size of olfactory mucosa 95–126 cm2 (German Shepherd) [124]
Olfactory genes in genome > 1000; 80% functional receptor genes and 20% pseudogenes [125]
Amount of olfactory receptor cells (ORCs) 200–300 million in nasal cavity [58, 59]
Cilia per ORC 20 to 100 cilia per cell [58]
Extent, shape and position of olfactory bulb Proportionally larger than in humans and prominently at the ventro-rostral area of the brain [126]
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Jendrnyetal. BMC Infect Dis (2021) 21:838
meningoencephalitis or head trauma [102], general
inflammation and systemic diseases, exposure to dust
and toxic chemicals/materials, uraemia and blood flow
changes as well as the hydration state [103]. Different
infections of the upper respiratory tract, e.g. SARS-
CoV-2-infections, can also cause anosmia in humans
[104]. Whether dogs play a role in the infection inci-
dence of SARS-CoV-2 is controversially discussed in
the literature and there is no evidence that dogs might
be affected by anosmia through a SARS-CoV-2-infec-
tion so far, but it also cannot be completely excluded by
now [105–107]. Dog-specific viral diseases like canine
distemper virus and canine parainfluenza virus [108]
cause conductive hyposmia by generating nasal inflam-
mation and increasing mucous secretion and result
in vascular congestion that alters the air flow. Fur-
thermore, allergic rhinitis and turbinate engorgement
caused by hypocapnia, cold air, irritating chemicals or
an increased parasympathetic tone result in olfactory
decrease or loss [109].
Some pharmaceuticals used in human medicine are
also applicable for dogs and may potentially have sim-
ilar effects in dogs [110]. Only specific effects of ster-
oids, antibiotics and anaesthetics on the dog’s olfaction
are documented in the scientific literature at this time
[58]. Other medications potentially endangering dog’s
olfaction are described elsewhere [58, 111–116].
Discussion
e special structure and physiology of the canine olfac-
tory system contain a huge potential of olfactory power
[58]. e dog’s sense of smell is mainly used to attract
prey and to perceive the environment but could also be
promoted and meaningfully used by humans for biomed-
ical purposes. Since the vomeronasal organ (VNO) has
an important function in intra-species communication or
the detection of pheromones and is capable of processing
a wide variety of molecules, it may be possible that direct
detection of viruses or viral proteins (not VOCs) by the
VNO occurs, thus representing a different mechanism of
odour perception. However, this is only a hypothesis and
has not yet been proven.
Various diagnostic studies have addressed the detec-
tion of different diseases by dogs. Despite the promising
results of the scent detection dogs, this method is only
marginally or not used in the field of human medicine.
e majority of medical professionals continues to rely
on diagnostic standard methods although the canine
medical detection method achieved equal or even higher
rates of diagnostic accuracy. For example, electronic
noses have a limit of detection of 100 to 400 parts per
Fig. 3 Sagittal magnetic resonance imaging highlighting the inner structures of the olfactory system. The blue area represents the vomeronasal
organ, the respiratory epithelium in the maxilloturbinates is highlighted in yellow, the olfactory epithelium in the ethmoturbinates near the lamina
cribrosa is shown in green, and the red area contains the bulbus olfactorius
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Jendrnyetal. BMC Infect Dis (2021) 21:838
billion (ppb) (1 × 10–7) [117] whereas the olfactory detec-
tion threshold of dogs is lower than 0.001ppb (1 × 10–12)
[71], so they surpass this technology by far. But incon-
sistent findings and the complexity of this research area
prevents the practitioners from including this method
in their daily routine. Moreover, a medical device or
health technology requires an approval by national health
organizations before permission for usage is granted. For
such approval, ethical, social, organisational, and legal
aspects are assessed alongside technological, economic
and safety aspects, as well as clinical effectiveness [5].
Other limitations of the medical scenting dog method
is the current lack of standardisation of the training and
deployment of biomedical detection dogs (although this
has been tried in several detection dog studies [5, 118]) as
each dog has an individual character, an individual train-
ing level or training requirements, and there are several
different breeds with a variation of characters and olfac-
tory thresholds. But there are legislated guidelines and
commission regulations for the use of explosive detec-
tion dogs, which could and should be used in a modified
form for biomedical detection dogs as well [119, 120]. In
addition, dogs are living creatures with varying detection
performances at different times. Moreover, the training
condition has to be maintained with regular training,
unlike in machines. Variation of detection accuracy may
be caused by failure in odour conditioning, lack of moti-
vation, inappropriate training methods (e.g. alternative
forced choice without blank trials [5]) or other confound-
ing factors [40]. A test run at the beginning of the detec-
tion work could reduce the error frequency of the dogs.
e disease detection dog studies differ in terms of exper-
imental setup, sample material (urine, breath, blood,
saliva, faeces, sweat/body odour) and sampling method,
individual dog characteristics, dog training methods and
evaluation strategies of the results. For some diseases like
different cancer types, the canine method seems to be
not very useful due to the need of reliable identification
of early, preclinical stages that require surgical interven-
tion. To reliably diagnose a certain disease, laboratory
testing or equivalent methods still have to be performed
because of the fact that the canine method is not gener-
ally accepted and approved.
e advantages of the canine method are especially
the non-invasiveness, speed, nearly immediate results,
effectiveness of testing, cost effectiveness, mobility, high
sensitivity and specificity of the dogs’ noses, safety for
persons to be tested and persons performing the test (dog
handlers), the simplicity and security of the sampling,
testing procedure, specimen storage and evaluation of
the results. Acquisition and training of a medical detec-
tion dog is maybe less cost-intensive than the purchase
of expensive high-tech equipment. e sample collec-
tion requires no special abilities of the performing person
and is not associated with any health risk for the patient
due to the non-invasiveness in contrast to some standard
methods. e samples can be preserved for some time
and presented to several dogs which may increase the
diagnostic accuracy. e sample material can be adapted
to the disease to be tested (disease-specific VOCs) and
even varied if necessary to reduce or eliminate the infec-
tion risk of the operating persons and dogs. e training
period for emerging diseases is much less time-consum-
ing than inventing a new technological test method. If
the training period is once completed, the testing pro-
cedure is easy and time saving. While testing, there are
four possibilities for the dogs to respond to the presented
samples: True positive means, the dog correctly indicates
Fig. 4 Three-dimensional computed tomographic reconstruction of
a canine skull. The arrows represent the airways, with the pink arrow
showing the common airflow and the red and blue arrows showing
the olfactory and respiratory airflow, respectively. The nostrils, the
olfactory and respiratory epithelium as well as the olfactory bulb, and
the tracheal tube are labeled. During inhalation the air flows from
the nares and the nasal vestibule to the maxilloturbinates, then into
the ethmoturbinates and the paranasal sinuses towards the pharynx
[122]. There is a major difference between breathing and sniffing
in dogs. While breathing, most of the inspired air flows through the
nasopharynx into the lungs but only a small percentage (12–13%)
reaches the olfactory areas [59]. The sniffing process generates
external (outside the nostrils) and internal (within the nasal cavity)
fluid dynamics. The ambient air is inhaled from the front and exhaled
to the side for efficient odorant sampling, whereas each nostril
samples separately. A sniff is the first critical step of the olfactory
process with the function of generating unique unidirectional
laminar airflow patterns to transport environmental odorants into the
nasal cavity to the olfactory epithelium [122]. Furthermore, sniffing
increases odour sensitivity and affects the intensity of odorants [60,
90]
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Jendrnyetal. BMC Infect Dis (2021) 21:838
a disease-positive sample; false positive means, the dog
incorrectly indicates a negative control or distractor sam-
ple; true negative: the dog correctly does not indicate a
negative control or distractor sample; and false negative:
the dog incorrectly does not indicate a positive sample.
For evaluation of the results and assessment of the diag-
nostic accuracy, the use of contingency tables can be
useful. For testing of unknown samples, the possible indi-
cations are of binary character (disease-positive or -nega-
tive). e effectiveness of the dog method is also a great
advantage. Dogs can screen large amounts of people in a
short time with high rates of diagnostic accuracy. After
a successful training phase, the dogs can be deployed in
any setting or terrain, whereas most technological meth-
ods require standardised environmental conditions to
function reliably, highlighting mobility as another mean-
ingful advantage of the dogs. In summary, this method
has promising potential for the effective detection of var-
ious infectious and non-infectious diseases after major
limitations have been eliminated. Especially in countries
with a lack of access to high technology screening meth-
ods or as a preliminary mass screening for infectious dis-
eases at major events or airports the canine method has a
huge potential.
Conclusion
e use of biomedical detection dogs has many advan-
tages and potential, but also some limitations. e lit-
erature shows that detection dogs can be considered as
a screening method, especially for infectious diseases
but may not be considered as a substitute for standard
diagnostic methods until standardised and validated. In
order to use biomedical detection dogs as an approved
screening method for disease detection, the following
issues need to be addressed: Standardisation of training
and deployment techniques (ensuring generalisation to
specific disease stages, symptomatic and asymptomatic
patients), reproducibility within and between detec-
tion dogs, and (re-)certification by an official body. At
this time, it should be recognised as an additional non-
invasive, rapid diagnostic tool to effectively detect early
stages of specific diseases in great confluences of people.
Additional research is necessary to create a standardised,
operationally viable system for canine olfactory detec-
tion of various human diseases. In addition, the ability
of dogs to be able to discriminate between healthy and
diseased patients can support identification of diseases in
which VOCs could be characterised, e.g. via GC–MS like
in Sethi etal. [121] for the development of different VOC
based test systems.
Abbreviations
VOC: Volatile organic compound; COVID-19: Coronavirus disease 2019; OR:
Olfactory receptor; ORC: Olfactory receptor cell; ppb: Parts per billion.
Acknowledgements
We would like to thank Antja Watanangura for the artwork.
Authors’ contributions
PJ drafted the manuscript and did most of the literature review. FT, SM, and
HAV also drafted the manuscript, helped with the literature review, and the
design of the article. ES provided helpful input regarding the training and
deployment of biomedical detection dogs. All authors read and approved the
final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or
analysed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1 Department of Small Animal Medicine and Surgery, University of Veterinary
Medicine Hannover, Bünteweg 9, 30559 Hannover, Germany. 2 Research Center
for Emerging Infections and Zoonoses, University of Veterinary Medicine Han-
nover, Bünteweg 17, 30559 Hannover, Germany. 3 Bundeswehr School of Dog
Handling, Gräfin-Maltzan-Kaserne, Hochstraße, 56766 Ulmen, Germany.
Received: 17 May 2021 Accepted: 3 August 2021
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